Project Summary The function of the intervertebral disc is mechanical. but disc pathology and LBP is currently evaluated in terms of structural changes, ?structural degeneration (s-degen)?, observed from static images, and not in terms of mechanical function changes. While s-degen is considered to be related to pathology, it has had little clinical success discriminating pathology from natural aging. Ex vivo studies have found s-degen is related to progressive degradation of material properties that implies loss of mechanical function, ?functional degeneration (f-degen)?, but f-degen remains unquantified in vivo because there is no technique to measure it. Lack of information regarding in vivo mechanics hinders matching symptoms to individual discs and, furthermore, translation of ex vivo results and models to the in vivo context. To study and treat LBP, a technique needs to be developed to quantify disc mechanical function in vivo. MRI is the preferred non- invasive platform to study and diagnose disc health. Unfortunately, current MRI assessment based on a single supine posture is insufficient to assess disc mechanical function. Mechanical function must be determined by how the disc responds to changes in loading state. Therefore, MRI studies of the disc performed under loading states brought about by different spine positions could be used to quantify disc mechanics in vivo. There is a critical need to develop and apply a quantitative, noninvasive in vivo assessment of disc mechanical function and f-degen. The consequence of failing to address this need is hindering efforts to determine mechanisms of disc pathology and to develop and assess new therapies. The goal of this proposal, is to noninvasively quantify disc mechanical function in vivo and establish a new degeneration classification that incorporates f-degen (mechanical function changes) in addition to subject traits (age, sex) and s-degen (structural changes), and to predict the disc's internal stress and strain for in vivo movements. The central hypothesis is that aging and disc degeneration are related to altered mechanical function as assessed in vivo from changes in MRI variables with prescribed loading (morning-to-evening and supine-to-flexed/extended). We propose to: Aim 1: Quantify functional degeneration (f-degen) from in vivo MRI changes between loading states. Aim 2: Create an ex vivo ? in vivo translation by replicating in vivo deformation states in separate ex vivo donor specimens. Correlate MRI f-degen with degradation in disc- and tissue-scale material properties. Aim 3: Predict disc stress and strain for in vivo movements using a finite element model linked to MRI. Completion of these aims will yield a new in vivo image-based statistical classification of normal and degenerative disc function. It will provide meaningful and predictive relationships describing human disc physiology and pathophysiology, replacing the inadequate structural grading systems that are the current standard, and will provide new capabilities to measure and predict disc biomechanics in vivo.